This application claims the benefit of the filing date of German Patent Application Number 10054481.9, filed on Nov. 3, 2000, which application is hereby incorporated by reference.
One embodiment of the present invention relates to acylaminoalkyl-substituted benzenesulfonamide derivatives of the formula (I), 
in which A, R(1), R(2), X, Y and Z have the meanings indicated below. The compounds of the formula (I) are valuable pharmaceutically active compounds that have, for example, an inhibitory action on ATP-sensitive potassium channels in the cardiac muscle and/or in the vagal cardiac nerve and are suitable, for example, for the treatment of disorders of the cardiovascular system such as coronary heart disease, arrhythmias, cardiac insufficiency, cardiomyopathies, decreased contractility of the heart or vagal dysfunction of the heart, or for the prevention of sudden cardiac death. Another embodiment of the invention relates to processes for the preparation of compounds of the formula (I), their use and pharmaceutical preparations comprising them.
For certain benzenesulfonylureas, a blood-sugar-lowering action has been described. A prototype of such blood-sugar-lowering sulfonylureas is glibenclamide, which is used therapeutically as an agent for the treatment of diabetes mellitus. Glibenclamide blocks ATP-sensitive potassium channels and is used in research as a tool for the exploration of potassium channels of this type. In addition to its blood-sugar-lowering action, glibenclamide has other actions that are attributed to the blockade of precisely these ATP-sensitive potassium channels but that hitherto can still not be used therapeutically. These include, for example, an antifibrillatory action on the heart. In the treatment of ventricular fibrillation or its early stages with glibenclamide however, the marked blood-sugar-lowering simultaneously produced by this substance would be undesirable or even dangerous, as it can further worsen the condition of the patient, so that glibenclamide is not suitable clinically as an antiarrhythmic.
Various patent documents, for example U.S. Pat. No. 5574069, U.S. Pat. No. 5698596, U.S. Pat. No. 5476850, U.S. Pat. No. 5652268 or WO-A-00/03978, disclose antifibrillatory benzenesulfonylureas and -thioureas having reduced blood-sugar-lowering action. WO-A-00/15204 describes the action of some of these compounds on the autonomic nervous system. The properties of these compounds, however, are still not satisfactory in various respects, and there is an ongoing need for compounds having a more favorable pharmacodynamic and pharmacokinetic property profile that are better suited, for example, for the treatment of a disturbed cardiac rhythm and its consequences such as sudden cardiac death or a weakened myocardial contractile force.
Various benzenesulfonylureas having an acylaminoalkyl substituent, in which the acyl group can also be derived, inter alia, from cinnamic acids, and the blood-sugar-lowering action of these compounds are disclosed in DE-A-1443878, U.S. Pat. No. 3454636, DE-A-1518877 and U.S. Pat. No. 4066639. The benzenesulfonylureas that are described in GB-A-1116355 are just so characterized by a blood-sugar-lowering action, among them some specific benzenesulfonylureas that contain a heteroarylacryloyl-aminoalkyl group in the para position to the sulfonylurea group. In WO-A-00/71513 (international patent application PCT/EP00/04091) certain cinnamoylaminoalkyl-substituted benzenesulfonamide derivatives are described, which are distinguished by a marked action on ATP-sensitive potassium channels in the heart. Further investigations showed that the benzenesulfonamide derivatives of the present invention, which contain acylaminoalkyl substituent in the meta position to the sulfonyl group, show a marked action on ATP-sensitive potassium channels of the cardiac muscle and/or of the vagal cardiac nerve, without having a marked action on pancreatic potassium channels and thus are valuable pharmaceutical active compounds, for example, for the treatment of disorders of the cardiovascular system.
Another embodiment of the present invention relates to compounds of the formula(l), 
in which
R(1) is
1) (C1-C4)-alkyl; or
2) xe2x80x94Oxe2x80x94(C1-C4)-alkyl which is unsubstituted or is substituted by 1, 2 or 3 fluorine atoms; or
3) xe2x80x94Oxe2x80x94(C1-C4)-alkyl which is substituted by a substituent chosen from nitro, ((C1-C4)-alkyl)carbonylamino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, hydroxycarbonyl, ((C1-C4)-alkoxy)carbonyl, piperidin-1-yl, morpholin-4-yl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, and phenoxy; where the phenyl group and the phenoxy group are unsubstituted or are substituted by one or two identical or different substituents chosen from halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, and trifluoromethyl; or
4) xe2x80x94Oxe2x80x94(C1-C4)-alkyl-E(1)-(C1-C4)-alkyl-D(1), in which D(1) is hydrogen or xe2x80x94E(2)-(C1-C4)-alkyl-D(2), in which D(2) is hydrogen or xe2x80x94E(3)-(C1-C4)-alkyl, where E(1), E(2) and E(3), which are independent of one another and can be identical or different, are O, S, or NH; or
5) xe2x80x94Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94(C1-C4)-alkyl, which is substituted in the terminal alkoxy group by 1, 2 or 3 fluorine atoms; or
6) xe2x80x94Oxe2x80x94(C2-C4)-alkenyl; or
7) xe2x80x94O-phenyl which is unsubstituted or is substituted by one or two identical or different substituents chosen from halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, and trifluoromethyl; or
8) halogen; or
9) phenyl, which is unsubstituted or is substituted by one or two identical or different substituents chosen from halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, xe2x80x94S(O)mxe2x80x94(C1-C4)-alkyl, phenyl, amino, hydroxyl, nitro, trifluoromethyl, cyano, hydroxycarbonyl, carbamoyl, ((C1-C4)-alkoxy)carbonyl, and formyl; or
10) (C2-C5)-alkenyl, which is unsubstituted or is substituted by a substituent chosen from phenyl, cyano, hydroxycarbonyl, and ((C1-C4)-alkoxy)carbonyl; or
11) (C2-C5)-alkynyl, which is unsubstituted or is substituted by a substituent chosen from phenyl and (C1-C4)-alkoxy; or
12) 5-membered or 6-membered monocyclic heteroaryl having one or two identical or different ring heteroatoms chosen from oxygen, sulfur, and nitrogen; or
13) xe2x80x94S(O)m-phenyl which is unsubstituted or is substituted by one or two identical or different substituents chosen from halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, and trifluoromethyl;
R(2) is hydrogen, (C1-C6)-alkyl or (C3-C7)-cycloalkyl, but is not hydrogen if Z is oxygen;
the residues R(3), which are all independent of one another and can be identical or different, are hydrogen or (C1-C3)-alkyl;
A is one of the following residues: 
in which the free bond via which the residue is bonded to the amino group in the formula (I) is represented by the symbol ;
X is oxygen or sulfur;
Y is xe2x80x94(CR(3)2)2)nxe2x80x94;
Z is NH or oxygen;
m is 0, 1 or 2;
n is 1, 2, 3 or 4;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
If groups, residues, substituents or variables can occur several times in the compounds of the formula (I), they can all independently of one another have the meanings indicated and can in each case be identical or different.
The term alkyl denotes straight-chain or branched saturated hydrocarbon residues. This also applies to groups derived therefrom such as, for example, alkoxy, alkoxycarbonyl or the residue xe2x80x94S(O)m-alkyl. Examples of alkyl residues Include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 1-methyl-butyl, isopentyl, neopentyl, tert-pentyl, n-hexyl or isohexyl. Examples of alkoxy include methoxy, ethoxy, propoxy such as n-propoxy and isopropoxy, butoxy such as n-butoxy, isobutoxy and tert-butoxy, etc. The same applies correspondingly to substituted alkyl residues, for example phenylalkyl residues, and to divalent alkyl residues (alkanediyl residues), in all of which the substituents or the bonds, via which the residues are bonded to the neighboring groups, can be situated in any desired positions. Examples of alkyl residues of this type, which are bonded to two neighboring groups, include xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 all of which, inter alia, can represent the group Y or can be present in a group xe2x80x94Oxe2x80x94(C1-C4)-alkyl which carries one substituent.
Alkenyl and alkynyl are straight-chain or branched, monounsaturated or polyunsaturated hydrocarbon residues, in which the double bonds and/or triple bonds can be situated in any desired positions. For example, the residues alkenyl and alkynyl may contain one double bond or one triple bond. Examples of alkenyl and alkynyl include vinyl, prop-2-enyl (allyl), prop-1-enyl, but-2-enyl, but-3-enyl, 3-methyl-but-2-enyl, pent-2,4-dienyl, ethynyl, prop-2-ynyl (propargyl), prop-1-ynyl, but-2-ynyl and but-3-ynyl. In substituted alkenyl residues and alkynyl residues the substituents can be situated in any desired positions.
Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl all of which can also be substituted by one or more, for example one, two, three or four, identical or different (C1-C4)-alkyl residues, for example methyl residues.
Halogen is fluorine, chlorine, bromine, or iodine, for example, chlorine or fluorine.
In substituted phenyl residues the substituents can be situated in any desired positions. In monosubstituted phenyl residues the substituent can be situated in the 2-position, the 3-position, or the 4-position. In disubstituted phenyl residues the substituents can be situated in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. If a phenyl residue carries a further phenyl residue as a substituent, then this second phenyl residue can also be unsubstituted or can be substituted by the substituents indicated for the first phenyl residue, apart from a phenyl residue.
The heteroaryl residues, which are derived from monocyclic 5-membered or 6-membered aromatic ring systems, can also be regarded as residues derived from cyclopentadienyl or phenyl by replacement of one or two CH groups and/or CH2 groups by S, O, N, NH (or N carrying a substituent such as, for example, Nxe2x80x94CH3), the aromatic ring system being retained or an aromatic ring system being formed. In addition to the one or two ring heteroatoms, they contain three to five ring carbon atoms. Examples of heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, 1,3-oxazolyl, 1,2-oxazolyl, 1,3-thiazolyl, 1,2-thiazolyl, pyridyl, pyrazinyl, pyrimidyl or pyridazinyl. A heteroaryl residue can be bonded via any ring carbon atom. For example, a thienyl residue can be present as a 2-thienyl residue or 3-thienyl residue, a furyl residue as a 2-furyl residue or 3-furyl residue, a pyridyl residue as a 2-pyridyl residue, 3-pyridyl residue or 4-pyridyl residue. A residue derived from 1,3-thiazole or from imidazole can be bonded via the 2-position, the 4-position, or the 5-position. Suitable nitrogen heterocycles can also be present as N-oxides or as quaternary salts with an anion derived from a physiologically tolerable acid as counter ion. Pyridine rings can thus also be present, for example, as pyridine N-oxides.
A tetrahydrofuranyl residue can be bonded via the 2-position or the 3-position, a tetrahydropyranyl residue via the 2-position, the 3-position or the 4-position. Examples of tetrahydrofuranyl and tetrahydropyranyl residues include tetrahydrofuran-2-yl and tetrahydropyran-2-yl.
Another embodiment of the present invention comprises all stereoisomeric forms of the compounds of the formula (I). Asymmetric centers present in the compounds of the formula (I) can all independently of one another have the S configuration or the R configuration. The invention includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers, in all ratios. Enantiomers, for example, thus are a subject of the invention in enantiomerically pure form, as levorotatory as well as dextrorotatory antipode, in the form of the racemate and in the form of mixtures of the two enantiomeric forms in all ratios. In the presence of cis/trans isomerism or E/Z isomerism, the cis form, the trans form, the E form, the Z form and mixtures of these forms in all ratios are another subject of the invention. Individual stereoisomers can be prepared, if desired, by resolution of a mixture according to customary methods, for example by chromatography or crystallization, or by use of stereochemically uniform starting substances in the synthesis, or by stereoselective reactions. If appropriate, a derivatization can be carried out before separation of stereoisomers. The separation of a stereoisomer mixture can be carried out at the stage of the compounds of the formula (I) or at the stage of an intermediate in the course of the synthesis. The invention also comprises all tautomeric forms of the compounds of the formula (I).
Physiologically tolerable salts of the compounds of the formula (I) include nontoxic salts or pharmaceutically utilizable salts. They can contain inorganic or organic salt components. Such salts can be prepared, for example, from compounds of the formula (I) that contain one or more acidic groups, and nontoxic inorganic or organic bases. Possible bases include, for example, suitable alkali metal compounds or alkaline earth metal compounds, such as sodium hydroxide or potassium hydroxide, or ammonia or organic amino compounds or quaternary ammonium hydroxides. Reactions of compounds of the formula (I) with bases for the preparation of the salts are in general carried out according to customary procedures in a solvent or diluent. On account of the physiological and chemical stability, advantageous salts in the presence of acidic groups include in many cases sodium, potassium, magnesium or calcium salts or ammonium salts that can carry one or more organic residues on the nitrogen. Salt formation on the nitrogen atom of the benzenesulfonamide group in this case leads to compounds of the formula (II), 
in which A, R(1), R(2), X, Y, and Z have the meanings indicated above and the cation M, for example, is an alkali metal ion or an equivalent of an alkaline earth metal ion, for example the sodium, potassium, magnesium, or calcium ion, or the unsubstituted ammonium ion or an ammonium ion having one or more organic residues. An ammonium ion representing M can, for example, also be the cation that is obtained from an amino acid, for instance a basic amino acid such as, for example, lysine or arginine, by protonation.
Compounds of the formula (I) that contain one or more basic, i.e. protonatable, groups, can be present and can be used according to the invention in the form of their acid addition salts with physiologically tolerable inorganic or organic acids, for example as salts with hydrogen chloride, phosphoric acid, sulfuric acid or organic carboxylic acids or sulfonic acids such as, for example, p-toluenesulfonic acid, acetic acid, tartaric acid, benzoic acid, fumaric acid, maleic acid, citric acid etc. Acid addition salts can also be obtained from the compounds of the formula (I) according to customary processes known to the person skilled in the art, for example by combination with an organic or inorganic acid in a solvent or diluent. If the compounds of the formula (I) simultaneously contain acidic and basic groups in the molecule, the present invention also comprises internal salts or betaines (zwitterions), in addition to the salt forms described. The present invention also comprises all salts of the compounds of the formula (I) that, because of low physiological tolerability, are not directly suitable for use in pharmaceuticals but can be used, for example, as intermediates for chemical reactions or for the preparation of physiologically tolerable salts, for example by anion exchange or cation exchange.
The present invention furthermore comprises all solvates of compounds of the formula (I), for example hydrates or adducts with alcohols, and also derivatives of the compounds of the formula (I) such as, for example, esters and amides of acid groups, and prodrugs and active metabolites of compounds of the formula (I).
In one embodiment of the present invention, the acyl residue A is a quinoline-3-carbonyl residue. The residue Axe2x80x94NHxe2x80x94 contained in the respective compounds, which is bonded to the group Y in the formula (I), can be designated, for example, as a 3-quinolinecarboxamido residue or a quinoline-3-carbonylamino residue. In a further embodiment of the present invention, the acyl residue A is a 1-cyclohex-1-enecarbonyl residue. The residue Axe2x80x94NHxe2x80x94 contained in the respective compounds, which is bonded to the group Y in the formula I, can be designated, for example, as a 1-cyclohex-1-enecarbonylamino residue or a 1-cyclohex-1-enecarboxamido residue (or also as a cyclohex-1-enecarboxamido residue). In a further embodiment of the present invention, the acyl residue A is a 3-methylbut-2-enoyl residue. The residue Axe2x80x94NHxe2x80x94 contained in the respective compounds, which is bonded to the group Y in the formula I, can be designated, for example, as a 3-methylbut-2-eneamido residue or a 3-methylbut-2-enoylamino residue (or also as 3,3-dimethylacryloylamino residue).
In one embodiment of the invention, in compounds of the formula (I) Z is oxygen and X is oxygen.
Y may be the residue xe2x80x94(CR(3)2)nxe2x80x94 in which the residues R(3) are hydrogen or methyl, for example, hydrogen. n may be 2 or 3, for example, 2. An example of the group Y is the group xe2x80x94CH2xe2x80x94CH2xe2x80x94.
Z may be NH. Examples of compounds of the formula (I) include the benzenesulfonamide derivatives of the formula (Ia), 
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. A subgroup of these compounds is formed by the benzenesulfonylthiourea derivatives of the formula (Ib), 
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts, another subgroup is composed by the benzenesulfonylurea derivatives of the formula (Ic), 
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. In the formulae (Ia), (Ib), and (Ic) the residues A, R(1), R(2), X and Y have the meanings indicated above. Another subgroup of the compounds according to the invention is formed by compounds of the formula (I) in which X is oxygen, Z is NH, and R(2) is methyl.
Examples of a (C1-C4)-alkyl residue representing R(1) include methyl, ethyl, and isopropyl.
An unsubstituted xe2x80x94Oxe2x80x94(C1-C4)-alkyl residue representing R(1) may include, for example, one of the residues methoxy, ethoxy, and propoxy for example methoxy or ethoxy. The alkyl group in a substituted xe2x80x94Oxe2x80x94(C1-C4)-alkyl residue representing R(1) may include, for example, a methyl group or an ethyl group that is substituted in the 2-position. A fluorine-substituted xe2x80x94Oxe2x80x94(C1-C4)-alkyl residue representing R(1) may include, for example, one of the residues trifluoromethoxy, 2-fluoroethoxy and 2,2,2-trifluoroethoxy, for example trifluoromethoxy. A substituted xe2x80x94Oxe2x80x94(C1-C4)-alkyl residue representing R(1), that carries a substituent other than fluorine atoms, may carry, for example, one of the substituents ((C1-C4)-alkyl)carbonylamino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, piperidin-1-yl, morpholin4-yl, tetrahydrofuranyl, tetrahydropyranyl, phenoxy, and phenyl, for example morpholin-4-yl, tetrahydrofuranyl, tetrahydropyranyl, phenoxy, and phenyl, including tetrahydrofuranyl, tetrahydropyranyl, and phenyl, where the phenyl group and the phenoxy group can in each case be unsubstituted or substituted as indicated, for example unsubstituted. Examples of xe2x80x94Oxe2x80x94(C1-C4)-alkyl residues that carry a substituent other than fluorine atoms include tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2-ylmethoxy, 2-(morpholin4-yl)ethoxy, 2-phenoxyethoxy, benzyloxy and 2-phenylethoxy, for example tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2-ylmethoxy and benzyloxy.
In one embodiment of the invention, in the residue xe2x80x94Oxe2x80x94(C1-C4)-alkyl-E(1)-(C1-C4)-alkyl-D(1) representing R(1), the groups E(1), E(2) and E(3) that can be present therein are oxygen. D(1) may be, for example, hydrogen. If D(1) has a meaning other than hydrogen, D(2) may be, for example, hydrogen. Examples of the residue xe2x80x94Oxe2x80x94(C1-C4)-alkyl-E(1)-(C1-C4)-alkyl-D(1) include xe2x80x94Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94(C1-C4)-alkyl and xe2x80x94Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94(C1-C4)-alkyl, for instance Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94(C1-C4)-alkyl, such as 2-methoxyethoxy, 2-ethoxyethoxy, and 2-(2-methoxyethoxy)ethoxy, for example 2-methoxyethoxy and 2-ethoxyethoxy.
In the residue xe2x80x94Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94(C1-C4)-alkyl representing R(1) in which the terminal alkoxy group, i.e. the alkoxy group that is not directly bonded to the benzene ring in the formula (I), is substituted by fluorine atoms, the fluorine-substituted alkoxy group may be one of the groups trifluoromethoxy and 2,2,2-trifluoroethoxy. Examples of a fluorine-substituted xe2x80x94Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94(C1-C4)-alkyl residue representing R(1) include xe2x80x94Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94CF3 or xe2x80x94Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94CH2xe2x80x94CF3, for example 2-(trifluoromethoxy)ethoxy or 2-(2,2,2-trifluoroethoxy)ethoxy.
An example of a residue xe2x80x94Oxe2x80x94(C2-C4)-alkenyl representing R(1) may be allyloxy.
A residue xe2x80x94O-phenyl representing R(1) may be, for example, unsubstituted or monosubstituted phenoxy, for example, phenoxy that is unsubstituted or substituted in the 4-position, including unsubstituted phenoxy, 4-methylphenoxy, 4-methoxyphenoxy, 4-fluorophenoxy or 4-trifluoromethylphenoxy.
Halogen representing R(1) may be, for example, bromine or iodine.
A phenyl residue representing R(1) may be, for example, unsubstituted or monosubstituted phenyl, including phenyl that is unsubstituted or substituted in the 4-position, for instance, phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, or 4-trifluoromethylphenyl, for example, unsubstituted phenyl.
A residue (C2-C5)-alkenyl representing R(1) may be, for example, allyl.
A residue (C2-C5)-alkynyl representing R(1) may be, for example, ethynyl.
A heteroaryl residue representing R(1) may contain, for example, one ring heteroatom, and may be for instance, a pyridyl residue, thienyl residue or furyl residue, including the residues 2-pyridyl, 3-pyridyl, 2-thienyl and 2-furyl.
A residue xe2x80x94S(O)m-phenyl representing R(1) may be, for example, unsubstituted or monosubstituted xe2x80x94S(O)m-phenyl, for instance unsubstituted xe2x80x94S(O)m-phenyl such as the unsubstituted residue xe2x80x94S-phenyl.
m may be, for example, 0 or 2, for instance 0.
In one embodiment of the invention R(1) is
1) methyl, ethyl, or isopropyl; or
2) methoxy, ethoxy, propoxy, trifluoromethoxy, 2-fluoroethoxy, or 2,2,2-trifluoroethoxy; or
3) tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2-ylmethoxy, 2-(morpholin-4-yl)ethoxy, 2-phenoxyethoxy, benzyloxy, or 2-phenylethoxy; or
4) 2-methoxyethoxy, or 2-ethoxyethoxy; or
5) 2-(trifluoromethoxy)ethoxy, or 2-(2,2,2-trifluoroethoxy)ethoxy; or
6) allyloxy; or
7) phenoxy, 4-fluorophenoxy, 4-methylphenoxy, 4-methoxyphenoxy, or 4-trifluoromethylphenoxy; or
8) bromine or iodine; or
9) phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, or 4-trifluoromethylphenyl; or
10) allyl; or
11) ethynyl; or
12) furyl, thienyl, or pyridyl; or
13) xe2x80x94S-phenyl.
In another embodiment of the invention R(1) includes those residues that are bonded via an oxygen atom to the benzene ring carrying the group R(1), and optionally substituted phenyl residue or heteroaryl residues. For example, R(1) may be one of the residues methoxy, ethoxy, trifluoromethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-(trifluoromethoxy)ethoxy, 2-(2,2,2-trifluoroethoxy)ethoxy, tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2-ylmethoxy, or benzyloxy.
If Z is NH, R(2) may be, for example, hydrogen, (C1-C4)-alkyl or cyclohexyl, including (C1-C4)-alkyl or cyclohexyl, such as methyl, ethyl, isopropyl, or cyclohexyl, for example methyl, ethyl or isopropyl. A specific subgroup of compounds of the formula (I) in which Z is NH is formed by compounds in which R(2) is hydrogen or methyl. If Z is oxygen, R(2) may be, for example, (C1-C4)-alkyl. In one embodiment of the invention R2 is methyl.
More examples of the compounds of the formula (I) include those in which one or more of the residues present therein have the meanings exemplified above. All combinations of exemplified substituent definitions are also a subject of the present invention. Another embodiment of the invention includes all stereoisomeric forms of the compounds of the formula (I) exemplified above and mixtures thereof in all ratios, and their physiologically tolerable salts.
Thus, for example, a group of exemplified compounds may be formed by those compounds of the formula (I) in which Z is NH, X is sulfur and R(2) is methyl, and the other residues have the general or exemplified meanings indicated above, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
Another subgroup of the compounds of the invention is formed by those compounds of the formula (I) in which
Y is xe2x80x94CH2xe2x80x94CH2xe2x80x94;
R(2) is methyl, ethyl, isopropyl or cyclohexyl;
and R(1), A, X and Z have the general or exemplified meanings indicated above, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. Examples of more subgroups of the compounds of the invention include those compounds formed by compounds of the formula (I) in which Z is NH and/or X is sulfur. One more subgroup of the compounds of the invention is formed by compounds in which R(2) is methyl.
Another embodiment of the invention includes compounds of the formula (I) in which
R(1) is methoxy, ethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, trifluoromethoxy, 2-(trifluoromethoxy)ethoxy, 2-(2,2,2-trifluoroethoxy)ethoxy, tetrahydrofuranylmethoxy, tetrahydropyranylmethoxy, or benzyloxy;
R(2) is methyl, ethyl, or isopropyl;
Z is NH;
and A, X and Y have the general or exemplified meanings indicated above, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
Another embodiment of the present invention relates to processes for the preparation of the compounds of the formula (I), which are illustrated below and according to which the compounds of to the invention are obtainable.
Compounds of the formula (I) in which X is sulfur and Z is NH, i.e. benzenesulfonylthioureas of the formula (Ib), 
in which A, R(1), R(2), and Y have the abovementioned meanings, can be prepared, for example, by reacting benzenesulfonamides of the formula (III), 
in which A, R(1), and Y have the abovementioned meanings, in an inert solvent or diluent with a base and with an R(2)-substituted isothiocyanate of the formula (IV)
R(2)-Nxe2x95x90Cxe2x95x90Sxe2x80x83xe2x80x83IV
in which R(2) has the meanings indicated above. Suitable bases include, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides or alkoxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, potassium amide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, or quaternary ammonium hydroxides. The reaction of the compound of the formula (III) with the base can initially be carried out in a separate step and the resulting salt of the formula (V), can also be intermediately isolated, if desired. 
In the compounds of formula (V), A, R(1) and Y have the abovementioned meanings and the cation M1 is an alkali metal ion, for example a sodium ion or potassium ion, or an equivalent of an alkaline earth metal ion, for example of a magnesium ion or calcium ion, or an ammonium ion which is inert under the reaction conditions, for example a quaternary ammonium ion. The salt of the formula (V), however, can also be produced in situ from the compound of the formula (III) and reacted directly with the isothiocyanate of the formula (IV). Suitable inert solvents for the reaction include, for example, ethers such as tetrahydrofuran (THF), dioxane, ethylene glycol dimethyl ether (DME) or diethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone, nitriles such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate; amides such as dimethylformamide (DMF), N-methylpyrrolidone (NMP), or hexamethylphosphoric triamide (HMPT), sulfoxides such as dimethylsulfoxide (DMSO); or hydrocarbons such as benzene, toluene or xylenes. Furthermore, mixtures of these solvents with one another are also suitable. The reaction of the compound of the formula (III) or (V) with the compound of the formula (IV) may be, for example, carried out at temperatures from room temperature to about 150xc2x0 C., including temperatures ranging from room temperature to about 100xc2x0 C.
Compounds of the formula (I) in which X is oxygen and Z is NH, i.e. benzenesulfonylureas of the formula (Ic), 
in which A, R(1), R(2) and Y have the abovementioned meanings, can be prepared, for example, by reacting, analogously to the synthesis of the thiourea derivatives of the formula (Ib) described above, benzenesulfonamides of the formula (III) or their salts of the formula (V) in an inert solvent or diluent with a base and LAW OFFICES with an R(2)-substituted isocyanate of the formula (VI)
R(2)-Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83VI
in which R(2) has the meanings indicated above. The above illustrations of the reaction with isothiocyanates correspondingly apply to the reaction with the isocyanates.
Benzenesulfonylureas of the formula (Ic) can also be prepared from the benzenesulfonamides of the formula (III) or their salts of the formula (V) by reaction with R(2)-substituted 2,2,2-trichloroacetamides of the formula (VII),
Cl3Cxe2x80x94COxe2x80x94NHxe2x80x94R(2)xe2x80x83xe2x80x83VII
in which R(2) has the meanings indicated above, in the presence of a base in an inert, high-boiling solvent such as, for example, DMSO.
Benzenesulfonylureas of the formula (Ic) can also be prepared by means of a conversion reaction (desulfurization) from the corresponding benzenesulfonylthioureas of the formula (Ib). The replacement of the sulfur atom in the thiourea group of the compounds of the formula (Ib) by an oxygen atom can be carried out, for example, with the aid of oxides or salts of heavy metals or by use of oxidants such as hydrogen peroxide, sodium peroxide, or nitrous acid.
Benzenesulfonylureas and -thioureas of the formulae (Ic) and (Ib) can also be prepared by reaction of amines of the formula R(2)-NH2. in which R(2) has the abovementioned meanings, with benzenesulfonyl isocyanates and isothiocyanates of the formula (VIII) 
in which A,R(1), X and Y have the abovementioned meanings. The sulfonyl isocyanates of the formula (VIII) (X=oxygen) can be obtained from the benzenesulfonamides of the formula (III) according to customary methods, for example using phosgene. The sulfonyl isothiocyanates of the formula (VIII) (X=sulfur) can be prepared by reaction of the sulfonamide of the formula III with alkali metal hydroxides and carbon disulfide in an organic solvent, such as DMF, DMSO, or NMP. The di-alkali metal salt of the sulfonyldithiocarbamic acid obtained here can be reacted in an inert solvent using a slight excess of phosgene or of a phosgene substitute such as triphosgene or using a chioroformic acid ester (2 equivalents) or using thionyl chloride. The solution of the sulfonyl iso(thio)cyanate of the formula (VIII) obtained can be reacted directly with the appropriately substituted amine of the formula R(2)-NH2 or, if compounds of the formula (I) are to be prepared in which R(2) is hydrogen, can be reacted with ammonia.
Correspondingly, starting from benzenesulfonyl iso(thio)cyanates of the formula (VIII), by addition of alcohols of the formula R(2)-OH in which R(2) has the abovementioned meanings with the exception of hydrogen, compounds of the formula (I) can be prepared in which Z is oxygen, i.e. the benzenesulfonylurethane derivatives of the formula (Ih), 
in which A, R(1), R(2), X and Y have the abovementioned meanings, but R(2), as mentioned, is not hydrogen. Compounds of the formula (Ih) can also be prepared, for example, by reacting, analogously to the syntheses described above, benzenesulfonamides of the formula (III) or their salts of the formula (V) in an inert solvent, for example a high-boiling ether, with reactive carbonic acid derivatives, for example with chloroformic acid esters of the formula Clxe2x80x94COxe2x80x94OR(2) or pyrocarbonic acid diesters of the formula (R(2)Oxe2x80x94C(xe2x95x90O))2O in which R(2) has the abovementioned meanings with the exception of hydrogen. Starting from the compounds of the formula (Ih) in which X is oxygen, compounds of the formula Ic are in turn obtainable by reaction with the appropriate amine of the formula R(2)-NH2 in an inert, high-boiling solvent, for example toluene, at temperatures up to the boiling point of the respective solvent.
The benzenesulfonamides of the formula (III) as the starting compounds for the processes for the synthesis of the benzenesulfonamide derivatives of the formula (I) can be prepared according to or analogously to known methods such as are described in the literature, for example in standard works like Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart, and Organic Reactions, John Wiley and Sons, Inc., New York, and in the patent documents indicated above, the relevant parts of which are hereby incorporated by reference, if necessary with appropriate adjustment of the reaction conditions as is familiar to the person skilled in the art. Use can also be made in this case of variants that are known per se but not illustrated here in greater detail. In the synthesis, it may also be appropriate to temporarily block functional groups which would react in an undesired manner or give rise to side reactions by protective groups, or to employ them in the form of precursor groups which are only later converted into the desired groups. Strategies of this type are known to the person skilled in the art. Starting substances can, if desired, also be formed in situ in such a way that they are not isolated from the reaction mixture, but immediately reacted further.
Thus it is possible, for example, to react p-substituted benzene derivatives of the formula (IX), 
in which Y has the abovementioned meanings and R(0) is, for example, (C1-C4)-alkyl, (C1-C4)-alkoxy, bromine, or nitro, with trifluoroacetic anhydride in the presence of pyridine in an inert solvent such as, for example, THF to give compounds of the formula (X), 
in which Y and R(0) have the meanings indicated above.
Starting from the compounds of the formula (X) in which R(0) is nitro, it is possible by means of reduction of the nitro group using a reductant such as, for example, SnCl2xc3x972 H2O in an inert solvent such as ethyl acetate, diazotization of the resulting amino group and subsequent reaction of the intermediate diazonium compound according to processes known per se, such as are described, for example, in Larock, Comprehensive Organic Transformations, VCH, 1989, for example by reaction with potassium iodide for the preparation of the iodo compounds, to obtain the corresponding p-halogen-substituted compounds of the formula (XI), 
in which Y has the meanings indicated above and Hal is halogen.
The compounds of the formula (XI) and the compounds of the formula (X) in which R(0) is (C1-C4)-alkyl, (C1-C4)-alkoxy or bromine, which are collectively designated as compounds of the formula (XII), 
in which Y has the meanings indicated above and R(1a) is (C1-C4)-alkyl, (C1-C4)-alkoxy or halogen, can be converted in a known manner into the benzene sulfonamides of the formula (XIII), 
in which Y and R(1a) have the meanings mentioned. The preparation of the sulfonamides of the formula (XIII) from the compounds of the formula (XII) can be carried out in one, two or more steps. Examples include processes in which the acylamines of the formula (XII) are first converted by means of electrophilic reagents in the presence or absence of inert solvents or diluents at temperatures from about xe2x88x9220xc2x0 C. to about 120xc2x0 C., including temperatures from about 0xc2x0 C. to about 100xc2x0 C., into the 2,5-substituted benzenesulfonic acids or their derivatives such as, for example, the sulfonic acid halides. For this, it is possible, for example, to carry out sulfonations using sulfuric acids or oleum, or halosulfonations using halosulfonic acids such as chlorosulfonic acid, or reactions with sulfuryl halides in the presence of anhydrous metal halides, or reactions with thionyl halides in the presence of anhydrous metal halides with subsequent oxidations, carried out in a known manner, to give sulfonyl chlorides. If sulfonic acids are the primary reaction products, these can be converted into sulfonic acid halides either directly or after treatment with amines such as, for example, triethylamine or pyridine, or with alkali metal or alkaline earth metal hydroxides or with other suitable bases, in a manner known per se by means of acid halides such as, for example, phosphorus trihalides, phosphorus pentahalides, thionyl halides or oxalyl halides. The conversion of the sulfonic acid derivatives into the sulfonamides of the formula (XIII) is carried out in a manner known from the literature. For example, sulfonyl chlorides are reacted with aqueous ammonia in an inert solvent such as, for example, acetone at temperatures from about 0xc2x0 C. to about 100xc2x0 C.
For the preparation of compounds of the formula (I) in which R(1) is (C1-C4)-alkyl, (C1-C4)-alkoxy or halogen, the compounds of the formula (XIII) can be converted by treatment with an acid such as, for example, hydrochloric acid or sulfuric acid, if appropriate with addition of a polar organic solvent such as methanol or ethanol, at temperatures from about 0xc2x0 C. up to the boiling point of the solvent, into the compounds of the formula (XIV), 
in which R(1a) is (C1-C4)-alkyl, (C1-C4)-alkoxy or halogen and Y has the meaning indicated above.
For the preparation of compounds of the formula (I) in which R(1) is any of the other residues mentioned above, initially the sulfonamide group in suitable compounds of the formula (XIII) can be temporarily protected by conversion into the Nxe2x80x94(N,N-dimethylaminomethylene)sulfonamide group. For example, starting from compounds of the formula (XIII) the dimethylaminomethylene compounds of the formula (XV), 
in which Y has the meanings mentioned and R(1b) is (C1-C4)-alkoxy, bromine or iodine, can be prepared by reacting the compounds of the formula (XIII), for example, with N,N-dimethylformamide dimethyl acetal or reacting them with N,N-dimethyl-formamide in the presence of dehydrating agents such as thionyl chloride, phosphorus oxychloride or phosphorus pentachloride.
The compounds of the formula (XV) in which R(1b) is (C1-C4)-alkoxy can then be converted by ether cleavage into the phenols of the formula (XVI) 
in which Y is as defined above. This ether cleavage is carried out, for example, by treatment of the compounds of the formula (XV) in which R(1b) is methoxy with acids or with Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, aluminum trichloride, for instance boron tribromide, or their etherates, in an inert solvent such as, for example, dichloromethane.
The phenols of the formula (XVI) obtained can be converted into the compounds of the formula (XVII) 
in which Y has the abovementioned meanings and R(1c) is one of the residues xe2x80x94Oxe2x80x94(C1-C4)-alkyl-E(1)-(C1-C4)-alkyl-D(1), fluorine-substituted xe2x80x94Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94(C1-C4)-alkyl, substituted xe2x80x94Oxe2x80x94(C1-C4)-alkyl, xe2x80x94Oxe2x80x94(C2-C4)-alkenyl, or xe2x80x94O-phenyl. This conversion is carried out by means of an O-alkylation of the phenols of the formula (XVI) using appropriately substituted halogen compounds such as iodides or bromides or sulfonic acid esters such as methanesulfonic acid esters, p-toluenesulfonic acid esters or trifluoromethanesulfonic acid esters. The sulfonic acid esters are obtainable from the correspondingly substituted alcohols of the formula R(1c)-H according to standard processes, for example by using methanesulfonyl chloride in an inert solvent in the presence of a base such as potassium carbonate or cesium carbonate in the case of the methanesulfonic acid esters. For example, with (2-bromoethyl) methyl ether or benzyl bromide the compounds of the formula (XVII) and thus the final compounds of the formula (I) are obtained in which R(1c) and R(1), respectively, is 2-methoxyethoxy or benzyloxy. The O-alkylation is in general carried out in the presence of a base in an inert solvent at temperatures from about 0xc2x0 C. up to the boiling point of the solvent according to processes known per se.
The preparation of compounds of the formula (XVII) in which R(1c) is xe2x80x94O-phenyl can be carried out by means of an O-arylation of the phenols of the formula (XVI) with phenylboronic acids, for example with phenylboronic acid or with substituted phenylboronic acids such as 4-methoxyphenylboronic acid, in the presence of copper catalysts, for example copper(II) acetate. Analogous reactions are described, for example, in Tetrahedron Lett. 39 (1998), 2937, the relevant disclosure of which is hereby incorporated by reference.
Starting from the compounds of the formula (XV) in which R(1b) is bromine or iodine, the compounds of the formula (XVIII) 
can be obtained in which Y has the indicated meanings and R(1d) is one of the residues (C1-C4)-alkyl, phenyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, heteroaryl or xe2x80x94S(O)m-phenyl. The conversion into the compounds of the formula (XVIII) can be carried Gout by means of palladium-catalyzed Suzuki coupling using arylboronic acids, for example phenylboronic acid, 4-methoxyphenylboronic acid, or 4-methylthiophenylboronic acid, or heteroarylboronic acids, for example thienylboronic acid, or by means of Stille coupling using trialkylstannanes, for example tributylstannylfuran, trimethylstannylpyridine or ethinyltributylstannane. The Suzuki coupling is carried out in the presence of palladium (II) acetate and triphenylphosphine or tetrakis(triphenylphosphine)palladium and a base such as, for example, cesium carbonate or potassium carbonate. Corresponding reactions are described in the literature. The Stille coupling is carried out analogously to literature procedures using bis(triphenylphosphine)palladium(II) chloride as catalyst. The preparation of suitable stannanes is described, for example, in Tetrahedron 49 (1993) 3325, the relevant disclosure of which is hereby incorporated by reference. The preparation of compounds of the formula (XVIII) in which R(1d) is alkyl can be carried out by means of Pd(0)-catalyzed Nikishi-Kumada coupling of the compounds of the formula (XV) in which R(1b) is iodine with an appropriate organozinc derivative in the presence of 1,1xe2x80x2-bis(diphenylphosphino)ferrocene, palladium(II) acetate and copper(I) iodide as catalysts in an inert solvent. Corresponding couplings are described, for example, in Synlett 1996, 473, the relevant disclosure of which is hereby incorporated by reference.
Compounds of the formula (XVIII) in which R(1d) is xe2x80x94S-phenyl can be prepared, analogously to literature procedures, from the compounds of the formula (XV) in which R(1b) is iodine by means of a copper(l) iodide-catalyzed nucleophilic substitution reaction, using the sodium salt of the appropriate thiophenol. The thioether group introduced in this way, and just so thioether groups in other positions of the molecule of the formula (I) or of a synthetic intermediate, can be oxidized by standard processes to the sulfoxide group or to the sulfone group, for example by using a peracid such as m-chloroperbenzoic acid.
The subsequent removal of the dimethylaminomethylene group and of the trifluoroacetyl group functioning as a sulfonamide protective group and amino protective group, respectively, from the compounds of the formula (XVII) and (XVIII) then leads to the corresponding compounds having a H2Nxe2x80x94Y group and H2Nxe2x80x94SO2 group which, together with the compounds of the formula (XIV), are represented by the formula (XIX), 
in which Y and R(1) have the meanings indicated above for the formula(l). This removal of the protective groups can be carried out either under basic or under acidic conditions. This reaction may be carried out by treatment of the compounds of the formula (XVII) and (XVIII) in an inert solvent, for example an alcohol, with acids such as, for example, hydrochloric acid.
The benzenesulfonamides of the formula (XIX) are then acylated using carboxylic acid derivatives of the formula Axe2x80x94OH, in which the residue A has the meanings indicated above, to give the acylaminoalkyl-substituted benzenesulfonamides of the formula (III). The carboxylic acids of the formula Axe2x80x94OH are commercially available or can be prepared according to literature procedures. The acylation is in generally carried out by converting the carboxylic acid firstly into a reactive derivative, for example by reaction with N,Nxe2x80x2-carbonyldiimidazole in an inert solvent such as, for example, THF, dioxane or DMF, and subsequent reaction with the amine of the formula(XIX), if appropriate in the presence of a base such as triethylamine or pyridine. As reactive derivatives of the carboxylic acids also the acid halides or the acid anhydrides, for example, can be used. The reactions in this case may be carried out at temperatures from about 0xc2x0 C. up to the boiling point of the chosen solvent or diluent, including at room temperature. The acylation of the amines of the formula (XIX) using the carboxylic acids can also be carried out, for example, in the presence of condensing agents such as, for example, N,Nxe2x80x2-dicyclohexylcarbodiimide, O-((cyano(ethoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) or 1-benzotriazolyloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP).
The steps described for the preparation of the compounds of the formula (I) can also be carried out in another sequence. Depending on the substituents to be introduced in the individual steps, one or another variant may be more advantageous. Thus, for example, the preparation of the compounds of the formula (III) in which R(1) is one of the residues (C1-C4)-alkyl, phenyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, heteroaryl or xe2x80x94S(O)m-phenyl, can also be carried out in such a way that firstly a compound of the formula XIV in which R(1a) is iodine or bromine is converted by coupling with a carboxylic acid derivative and temporary protection of the sulfonamide group, as described above, into a compound of the formula (XX), 
in which A and Y are as defined for formula (I) and Hal1 is iodine or bromine. From the compound of the formula (XX), it is then possible by means of the Suzuki, Stille, or Nikishi-Kumada couplings described above using the appropriate abovementioned coupling components, to obtain the compounds of the formula (XXI), 
in which A, R(1d) and Y have the meanings indicated above. The compounds of the formula (XXI) can then be converted into the compounds of the formula III by removal of the sulfonamide protective group according to the process described above.
The compounds of the invention inhibit ATP-sensitive potassium channels and influence the action potential of cells, for example, muscle cells. The compounds of the invention have a normalizing action on a disturbed action potential, such as is present, for example, in the case of ischemia, and are suitable, for example, for the treatment and prophylaxis of disorders of the cardiovascular system, including arrhythmias and their sequelae, for example of ventricular fibrillation or sudden cardiac death. The activity of the compounds of the invention can be demonstrated, for in the model described below, in which the action potential duration on the papillary muscle of the guinea pig is determined.
In addition to their action on ATP-sensitive potassium channels in the cardiac muscle cell, the compounds of the invention also have an action on the peripheral and/or the central autonomic nervous system. The compounds of the invention influence ATP-sensitive potassium channels of the vagal nervous system and have a stimulating action on the vagal nervous system, for example, a stimulating action on the vagal nervous system of the heart due to inhibition of ATP-sensitive potassium channels in the cardiac nerve.
In the ideal case, an optimum interaction, adapted to the particular situation, exists between the vagal (or parasympathetic) nervous system (=depressing nervous system) and the sympathetic nervous system (=stimulating nervous system). In the case of disease, however, this interaction may be disturbed and a dysfunction of the autonomic nervous system may be present, i.e. an inequilibrium may exist between the activity of the vagal nervous system and the activity of the sympathetic nervous system. Sympathovagal inequilibrium is understood in general as meaning a hyperactivity of the sympathetic (=stimulating) nervous system and/or a hypoactivity of the vagal (=depressing) nervous system, where the two parts of the nervous system can reciprocally influence one another. In particular, it is known that a hypoactivity of the vagal system can result in a hyperactivity of the sympathetic system. To avoid damage to cells or organs of the body due to overshooting biological or biochemical processes which are stimulated by an excessively high activity of the sympathetic nervous system, it is therefore attempted in such cases to compensate for a sympathovagal inequilibrium, for example to restore the normal vagal activity by eliminating a vagal dysfunction or hypoactivity.
Examples of diseases that can be treated by eliminating a vagal dysfunction and thus compensating for a harmful sympathovagal inequilibrium, are organic heart diseases such as coronary heart disease, cardiac insufficiency and cardiomyopathies. Damages to health that result from an inequilibrium of the autonomic nervous system when the dysfunction affects the heart include, for example, weakening of the myocardial contractile force and fatal cardiac arrhythmias. The importance of the autonomic nervous system for sudden cardiac death in heart diseases was described, for example, by P. J. Schwartz (The ATRAMI prospective study: implications for risk stratification after myocardial infarction; Cardiac Electrophysiology Review 2 (1998) 38) or T. Kinugawa et al. (Altered vagal and sympathetic control of heart rate in left ventricular dysfunction and heart failure; Am. J. Physiol. 37 (1995) R310). Experimental investigations with electrical stimulation of the cardiac vagus or stimulating analogs of the vagal transmitter acetylcholine, for example carbachol, confirm the protective action of a vagal activation against fatal cardiac arrhythmias (see, for example, E. Vanoli et al., Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction; Circ. Res. 68 (1991) 1471).
A sympathovagal inequilibrium, however, can also occur, for example, as a result of a metabolic disorder, for example of diabetes mellitus (see, for example, A. J. Burger et al., Short- and long-term reproducibility of heart rate variability in patients with long-standing type I diabetes mellitus; Am. J. Cardiol. 80 (1997) 1198). A hypoactivity of the vagal system can also temporarily occur, for example in the case of oxygen deficiency, for example oxygen deficiency of the heart, which leads to a reduced secretion of vagal neurotransmitters, for example of acetylcholine.
On account of the surprising ability of the compounds of the invention to abolish a hypoactivity of the vagal system or to restore the normal vagal activity, these compounds offer an efficient possibility of reducing, eliminating or preventing dysfunctions of the autonomic nervous system, including in the heart, and their sequelae such as, for example, the disease conditions mentioned. The efficacy of the compounds of the invention in the abolition of dysfunctions of the autonomic nervous system, for example of a vagal dysfunction of the heart, can be demonstrated in the model of chloroform-induced ventricular fibrillation in mice described below.
The compounds of the formula (I) and their physiologically tolerable salts can be used in animals, such as mammals, including humans, as pharmaceuticals on their own, in mixtures with one another or in the form of pharmaceutical preparations. Mammals in which the compounds of the invention can be used or tested are, for example, monkeys, dogs, mice, rats, rabbits, guinea pigs, cats and larger farm animals such as, for example, cattle and pigs. The invention therefore also relates to the compounds of the formula (I) and their physiologically tolerable salts and their prodrugs for use as pharmaceuticals, and pharmaceutical preparations (or pharmaceutical compositions) that contain an efficacious dose of at least one compound of the formula (I) and/or of a physiologically tolerable salt thereof and/or of a prodrug thereof as active constituent and a pharmaceutically tolerable carrier, i.e. one or more pharmaceutically acceptable vehicles and/or excipients (additives). The invention furthermore relates to the use of the compounds of the formula (I) and/or their physiologically tolerable salts and/or their prodrugs for the treatment, including the therapy and prophylaxis, of the syndromes mentioned above or below, to their use for the production of pharmaceuticals for the treatment, including therapy and prophylaxis, of the syndromes mentioned above or below, and to methods for the treatment, including the therapy and prophylaxis, of the syndromes mentioned above or below which comprise administering an efficacious amount of at least one compound of the formula (I) and/or a physiologically tolerable salt and/or a prodrug thereof.
The pharmaceutical preparations can be intended for enteral or parenteral use and may contain 0.5 to 90 percent by weight of at least one compound of the formula (I) and/or its physiologically tolerable salts and/or its prodrugs. The amount of active compound of the formula (I) and/or its physiologically tolerable salts and/or its prodrugs in the pharmaceutical preparations may range from about 0.2 to about 1000 mg, including from about 0.2 to about 500 mg, and from about 1 to about 300 mg, per dose unit. The pharmaceutical preparations can be prepared in a manner known per se. For this, the compounds of the formula (I) and/or their physiologically tolerable salts and/or their prodrugs are mixed with one or more solid or liquid vehicles and/or excipients and, if desired, with other pharmaceutical active compounds, for example pharmaceutical active compounds having cardiovascular activity such as, for example, calcium antagonists, ACE inhibitors or i-blockers, and brought into a suitable dose form and administration form, which can then be used as a pharmaceutical in human medicine or veterinary medicine.
Possible vehicles include organic and inorganic substances that are suitable, for example, for enteral, for example oral or rectal, administration, or for parenteral administration, for example by intravenous, intramuscular or subcutaneous injection or infusion, or for topical or percutaneous administration, and do not react in an undesired manner with the compounds of the invention. Examples of vehicles include water, vegetable oils, waxes, alcohols such as ethanol, propanediol or benzyl alcohols, glycerol, polyols, polyethylene glycols, polypropylene glycols, glyceryl triacetate, gelatin, carbohydrates such as lactose or starch, stearic acid and its salts such as magnesium stearate, talc, lanolin, petroleum jelly, or mixtures of two or more vehicles, for example mixtures of water with one or more organic solvents such as mixtures of water with alcohols. Examples of pharmaceutical forms for oral and rectal administration, include tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, suppositories, solutions, including oily, alcoholic or aqueous solutions, syrups, juices, drops, suspensions, and emulsions. Examples of pharmaceutical forms for topical application include, ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions, and powders. As solvents for solutions including injection and infusion solutions, for example water or alcohols such as ethanol, isopropanol or 1,2-propanediol or their mixtures with one another or with water, among others, can be used. Further possible pharmaceutical forms include, for example, implants. The compounds of the formula (I) and their physiologically tolerable salts can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. Liposomal preparations are also suitable, for example, for topical application. As examples of excipients (or additives) which can be present in the pharmaceutical preparations, glidants, preservatives, thickeners, stabilizers, disintegrants, wetting agents, agents for achieving depot effect, emulsifiers, salts (for example for influencing the osmotic pressure), buffer substances, colorants, flavorings, and aromatizers may be mentioned. If desired, pharmaceutical preparations can also contain one or more further active compounds and/or, for example, one or more vitamins.
On account of their ability to inhibit ATP-sensitive potassium channels, for example in the heart, and/or to decrease or to eliminate an inadequate function of the vagal nervous system and thereby a vagal dysfunction or a dysfunction of the autonomic nervous system, for example in the heart, the compounds of the formula (I) and their physiologically tolerable salts and prodrugs are valuable pharmaceutical active compounds that are suitable not only as antiarrhythmics and for the control and prevention of the sequelae of arrhythmias, but also for treatment and prophylaxis in other heart diseases or disorders of the cardiovascular system. Examples of such diseases that may be mentioned include cardiac insufficiency, cardiomyopathies, cardiac hypertrophy, coronary heart disease, angina pectoris, ischemia, and vagal dysfunction of the heart including, for example, vagal dysfunction of the heart in diabetes mellitus. The compounds of the invention can generally be employed in the treatment of diseases that are associated with a dysfunction of the autonomic nervous system or a hypoactivity or dysfunction of the vagal nervous system, for example in the heart, or are caused by such a dysfunction or in whose treatment an increase in or normalization of the activity of the vagal nervous system is desired. The compounds of the invention can also be employed in diseases that are characterized by oxygen deficiency conditions, in cerebral vascular disorders, and in dysfunctions of the autonomic nervous system, for example vagal dysfunction in the heart, which occur as a result of a metabolic disorder such as, for example, diabetes mellitus.
The compounds of the invention are used as antiarrhythmics for the treatment of cardiac arrhythmias of very different origin, including the prevention of sudden cardiac death due to arrhythmia. Examples of arrhythmic disorders of the heart include supraventricular arrhythmias such as, for example, atrial tachycardia, atrial flutters, or paroxysomal supraventricular arrhythmias, or ventricular arrhythmias such as ventricular extrasystoles, including life-threatening ventricular tachycardia and the particularly dangerous fatal ventricular fibrillation. They are suitable, for example, in those cases where arrhythmias are the result of constriction of a coronary vessel such as occur, for example, in angina pectoris or during acute cardiac infarcts or as a chronic result of a cardiac infarct. They are, therefore, suitable for the prevention of sudden cardiac death in post-infarct patients. Further syndromes in which arrhythmias of this type and/or sudden cardiac death due to arrhythmia play a part include, for example, cardiac insufficiency or cardiac hypertrophy as a result of chronically raised blood pressure.
Moreover, the compounds of the invention are able to positively influence decreased contractility of the heart and a weakened myocardial contractile force. This can be a disease-related decline in cardiac contractility, such as, for example, in cardiac insufficiency, but includes also acute cases such as heart failure in the case of shock. The compounds of the formula (I) and their physiologically tolerable salts are suitable for improving cardiac function. For example, in a heart transplantation, under the influence of the compounds of the invention, the heart can resume its capability faster and more reliably after the operation has taken place. The same applies to operations at on the heart that necessitate temporarily stopping cardiac activity by means of cardioplegic solutions.
Owing to the fact that the compounds of the invention, in addition to their direct cardiac action, i.e. the effect on the action potential of the cardiac muscle cells, also have an indirect action on the nervous system of the heart or on the parts of the nervous system acting on the heart, they can decrease or prevent undesirable sequelae emanating from the nervous system or mediated by the nervous system in the respective syndrome present. On account of this, further damage to health such as a weakening of the myocardial contractile force or in some cases fatal cardiac arrhythmias such as ventricular fibrillation can be reduced or avoided. Owing to the elimination or reduction of the dysfunction of the autonomic nervous system, the compounds of the invention have the effect that the weakened myocardial contractile force is normalized again and that the cardiac arrhythmias that can lead to sudden cardiac death do no longer develop. By selecting compounds of the invention having a suitable profile of action with respect to direct cardiac action (=direct effect on the action potential of the cardiac muscle cells and on account of this a direct effect on the contractile force and a direct antiarrhythmic effect) on the one hand and the action on the cardiac nerves on the other hand, it is efficiently possible with the aid of the compounds of the invention to favorably influence heart diseases. Depending on the syndrome present, it can also be advantageous in this case to employ compounds of the invention that have only a relatively slight direct cardiac effect and, on account of this, for example, have only a relatively slight direct effect on the contractile force of the heart or the formation of arrhythmias, but can improve or normalize the myocardial contractile force or the cardiac rhythm by means of the effect on the autonomic nervous system.
As used here, treatment includes therapy for a particular disease, such as treating cardiac insufficiency. In this respect, treatment can mean successfully eliminating the disease, reducing the effects associated with it, and/or reducing its severity. Treatment also includes prevention and prophylaxis of the onset of a disease by treating patients falling into a risk group or category for developing a particular disease or by treating patients after a successful treatment to prevent reoccurrence of the treated disease. Those skilled in the art can routinely identify patients likely to present with a disease, thereby qualifying as candidates for prevention therapy, because of factors such as diet, habits (e.g., smoking), family history for the disease, etc.
The dose of the compounds of the formula (I) or their physiologically tolerable salts depends, as usual, on the circumstances of the particular individual case and is adjusted by the person skilled in the art according to the usual rules and procedures. It depends, for example, on the specific compound of the invention administered, its potency and duration of action, on the nature and severity of the individual syndrome, on the sex, age, weight and on the individual responsiveness of the human or animal to be treated, on whether treatment is to be acute or prophylactic or on whether further active compounds are administered in addition to compounds of the invention. An effective amount of a compound of the invention is an amount sufficient to bring about a desired effect. For example, in the context of inhibition of ATP-sensitive potassium channels, an effective amount of a compound of the invention would constitute an amount sufficient to inhibit ATP-sensitive potassium channels.
Normally, In the case of administration to an adult weighing about 75 kg it is possible to manage with a dose that is about 0.1 mg to about 100 mg per kg per day, including doses from about 1 mg to about 10 mg per kg per day (in each case in mg per kg of body weight). The daily dose can be administered in the form of a single oral or parenteral dose or divided into a number of individual doses, for example two, three or four doses. The administration can also be carried out continuously. If acute cases of cardiac arrhythmias are treated, for example in an intensive care unit, parenteral administration, for example by injection or by intravenous continuous infusion, can be advantageous. A dose range in critical situations then may be from about 1 to about 100 mg per kg of body weight per day. Depending on individual behavior, it may be necessary to deviate upward or downward from the doses indicated.
Apart from being used as pharmaceutically active compounds in human medicine and veterinary medicine, the compounds of the invention can also be employed, for example, as auxiliaries for biochemical investigations or as a scientific tool when a respective effect on ion channels is intended, or for the isolation or characterization of potassium channels. They can also be used for diagnostic purposes, for example in in-vitro diagnoses of cell samples or tissue samples. The compounds of the formula (I) and their salts can furthermore be used as chemical intermediates for the production of further pharmaceutical active compounds.
Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term xe2x80x9cabout.xe2x80x9d Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.